Prion diseases

Dr. Roos serves on the Scientific Advisory Board of Revalesio Corporation and a Drug Monitoring Board for a gene therapy study of Sarepta Therapeutics. He has also received consulting fees from Best Doctors and Guidepoint Network, and holds shares in Amgen, Merck, Ionis, and Express Scripts.

)John E Greenlee MD, editor. (Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.)Originally released October 27, 1993; last updated April 15, 2020; expires April 15, 2023

In this article, the author reviews the group of diseases known as prion diseases, also referred to as the subacute spongiform encephalopathies. These diseases have a subacute to chronic clinical course with a similar neuropathology. All the diseases are transmissible and induced by an abnormal misfolded form of the prion protein that is extremely resistant to physical and chemical inactivation. The unusual nature of the transmissible agent and the emergence of variant Creutzfeldt-Jakob disease (as a result of ingestion of contaminated beef) have had a significant impact on public health in addition to science and medicine. New diagnostic tests, such as protein misfolding cyclic amplification and real time quaking-induced conversion, and new ideas about treatment of the subacute spongiform encephalopathies are discussed.

Key points

• The transmissible subacute spongiform encephalopathies, or prion diseases, have a similar noninflammatory spongiform pathology and are caused by a similar transmissible agent -- an abnormal (“scrapie-like”) protease-resistant conformation of the prion protein (PrP), which is designated PrPSc.

• Sporadic human prion diseases include Creutzfeldt-Jakob disease and fatal insomnia. Prion diseases acquired by infection include kuru (a subacute cerebellar disease found in the Highlands of New Guinea that was spread by ritual endocannibalism), variant Creutzfeldt-Jakob disease, and iatrogenic Creutzfeldt-Jakob disease. Familial human prion diseases, which are 10% of the overall cases, include familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia.

• Creutzfeldt-Jakob disease is a subacute fatal disease with a clinical triad of dementia, myoclonus, and EEG abnormalities that is usually associated with other neurologic abnormalities, along with neuropathological evidence of neuronal loss, spongiform changes, and astrocytosis. A new test that makes use of protein misfolding cyclic amplification, real-time quaking-induced conversion (RT-QulC), has high sensitivity and specificity and is helpful in making the diagnosis.

• Prion diseases are transmissible after a prolonged incubation period by inoculating the infected CNS into nonhuman primates and other species via multiple routes of inoculation; however, transmission is most efficient with an intracerebral inoculation into a species identical to the source of the infected CNS tissue.

In March of 1957, D Carleton Gajdusek entered the kuru region in New Guinea where Vin Zigas was stationed as a medical officer (Liberski et al 2019). This led to the first clinical and neuropathological descriptions of kuru (Gajdusek and Zigas 1957; Klatzo et al 1959). In 1959, Hadlow, a veterinarian neuropathologist, noted the similarity between kuru and scrapie, a transmissible disease of sheep that had an extremely prolonged incubation period (Hadlow 1959). This prompted attempts to transmit kuru into nonhuman primates following intracerebral inoculation of affected CNS tissue and to the eventual successful transmission of this disease (Gajdusek et al 1966).

Kuru and a number of other human (eg, Creutzfeldt-Jakob disease) and animal (eg, scrapie, bovine spongiform encephalopathy, and chronic wasting disease) diseases are grouped together as prion diseases or transmissible subacute spongiform encephalopathies because of their similar clinical and pathologic features as well as their transmissibility by an unconventional agent (Gajdusek et al 1966; Prusiner 1997; Prusiner et al 1998). This review focuses on kuru and fatal familial insomnia, with some discussion of Creutzfeldt-Jakob disease. The transmission of these diseases is of special interest because of the noninflammatory nature of the clinical-pathologic syndrome, the long incubation period ("slow" virus infection), and the unusual nature of the transmissible agent, the prion. The prion agent consists of misfolded prion protein (PrP) that is misfolded and protease-resistant, PrPSc. The importance of these diseases was demonstrated by the receipt of the Nobel Prize in 1976 and 1997 by Gajdusek and Prusiner respectively.

Fatal familial insomnia was first described in 1986 (Lugaresi et al 1986). In 1992 fatal familial insomnia patients were demonstrated to carry a mutation in the PrP gene, PRNP, as is the case with individuals with other forms of familial prion diseases; for this reason, fatal familial insomnia was proposed to be a prion disease (Medori et al 1992). The transmission of fatal familial insomnia to experimental animals has confirmed its inclusion in this group of diseases (Tateishi et al 1995). A noninherited disease, called fatal sporadic insomnia, with a similar clinical and pathological phenotype to fatal familial insomnia has also been described (Mastrianni et al 1999; Abu-Rumeileh et al 2018). The prion diseases became more visible because of an epidemic of bovine spongiform encephalopathy (“mad cow” disease), found primarily in the United Kingdom, and the subsequent emergence of variant Creutzfeldt-Jakob disease. Variant Creutzfeldt-Jakob disease is thought to result from oral transmission of the bovine spongiform encephalopathy agent to humans. In addition, the recognition of chronic wasting disease as a prion disease of deer and elk in the United States has focused attention on prion diseases.

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